Mast cells (MCs), basophils, and lymphocytes are integral to the development of an allergic response. Degranulation of MCs and granulocytes, and cytokine production by T cells is induced primarily by cross-linking of the receptor for antigen. However, allergic inflammation may also be generated through activation of receptors coupled to heterotrimeric G proteins (GPCRs). The purpose of this study is to understand mechanisms of intracellular G-protein-coupled signal transduction in immune cells and subsequent pathways to inflammation. GPCRs activate heterotrimeric G proteins, which bind guanosine triphosphate (GTP) in exchange for guanosine diphosphate (GDP). The GTP-bound form of the G protein alpha subunit induces downstream signaling cascades, including intracellular calcium flux responsible for MC/basophil degranulation. This project focuses on a family of regulators of G protein signaling (RGS proteins), which inhibit the function of G alpha-i and G alpha-q, but not G alpha-s, proteins by increasing their GTPase activity. G alpha subunits oscillate between GDP- (inactive) and GTP- (active) bound forms based on ligand occupancy of the associated receptor. The GTPase accelerating (GAP) activity of RGS proteins limits the time of interaction of active G-alpha and its effectors, resulting in desensitization of GCPR signaling. Despite a growing body of knowledge concerning the biochemical mechanisms of RGS action, relatively little is known about the physiological role of these proteins in allergic inflammation. A major area of investigation is the recruitment of inflammatory cells to sites of allergic inflammation. Chemokines are a major class of compounds acting on GPCRs in leukocytes, which orchestrate cell trafficking during the immune response. We found that RGS16 is enriched in activated/effector T lymphocytes. We showed that RGS16 constrains pulmonary inflammation by regulating chemokine-induced T cell trafficking in response to challenge with the helminth Schistosoma mansoni. Naive RGS16-deficienct mice were primed for inflammation by accumulation of CCR10+ T cells in the lung. Upon pathogen exposure, these mice developed more robust granulomatous lung fibrosis than wild-type counterparts. Distinct Th2 or putative Th17 subsets expressing CCR4 or CCR10 accumulated more rapidly in lungs of Rgs16 gene-deleted mice following challenge and produced proinflammatory cytokines IL-13 and IL-17B. Th1 and Th2 cells lacking RGS16 migrated more than wild-type counterparts to the chemokines CXCL9 and CCL17, respectively. RGS16-deficient Th2 cells localized aberrantly in challenged lungs. T lymphocytes were partially excluded from lung granulomas in Rgs16 knockout mice, instead forming peribronchial/perivascular aggregates. Thus, RGS16-mediated confinement of T cells to Schistosome granulomas mitigates widespread cytokine-mediated pulmonary inflammation. A second research area is the mechanisms controlling basophil trafficking in allergic responses. Many allergens contain intrinsic proteolytic activity and bind protease activated GPCRs. We studied the response of immune cells including basophils and T cells to the model protease allergen papain. Although sensitization to protease allergens, such as papain, helminth infection, chronic allergic skin inflammation, and nasal rhinitis are associated with basophil recruitment to inflammed tissue or to draining lymph nodes (LNs), the precise role of these granulocytes in allergic inflammation is incompletely understood. Basophils have the capacity to present antigen to naive T cells and promote TH2 differentiation directly or indirectly through IL-4 production. We studied how papain induces basophil migration to LNs and the contribution of various leukocytes to papain-induced immune responses. We immunized mice in the footpad with papain and studied leukocyte recruitment and inflammatory cytokine and chemokine production in the draining popliteal LNs. Papain directly activated naive T cells through protease-activated receptor (PAR)2 to initiate a chemokine/cytokine program that includes CCL17, CCL22, and IL-4. Papain-triggered chemokine and cytokine production and basophil trafficking to LNs were dependent on both CD4 T cells and PAR2 and were strongly reduced in the absence of CCR4, the primary receptor for CCL17/CCL22.